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Am J Physiol Heart Circ Physiol 283: H92-H101, 2002. First published March 21, 2002; doi:10.1152/ajpheart.01066.2001
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Vol. 283, Issue 1, H92-H101, July 2002

Increasing P50 does not improve DO2CRIT or systemic VO2 in severe anemia

Otto Eichelbrönner, Mark D'Almeida, Andreas Sielenkämper, William J. Sibbald, and Ian H. Chin-Yee

A. C. Burton Vascular Biology Laboratory, University of Western Ontario, London, Ontario, Canada N6A 4G5


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Reducing the hemolobin (Hb)-O2 binding affinity facilitates O2 unloading from Hb, potentially increasing tissue mitochondrial O2 availability. We hypothesized that a reduction of Hb-O2 affinity would increase O2 extraction when tissues are O2 supply dependent, reducing the threshold of critical O2 delivery (DO2 CRIT). We investigated the effects of increased O2 tension at which Hb is 50% saturated (P50) on systemic O2 uptake (VO2 SYS), DO2 CRIT, lactate production, and acid-base balance during isovolemic hemodilution in conscious rats. After infusion of RSR13, an allosteric modifier of Hb, P50 increased from 36.6 ± 0.3 to 48.3 ± 0.6 but remained unchanged at 35.4 ± 0.8 mmHg after saline (control, CON). Arterial O2 saturations were equivalent between RSR13 and saline groups, but venous PO2 was higher and venous O2 saturation was lower after RSR13. Convective O2 delivery progressively declined during hemodilution reaching the DO2 CRIT at 3.4 ± 0.8 ml · min-1 · 100 g-1 (CON) and 3.6 ± 0.6 ml · min-1 · 100 g-1 (RSR13). At Hb of 8.1 g/l VO2 SYS started to decrease (CON: 1.9 ± 0.1; RSR13: 1.8 ± 0.2 ml · min-1 · 100 g-1) and fell to 0.8 ± 0.2 (CON) and 0.7 ± 0.2 ml · min-1 · 100 g-1 (RSR13). Arterial lactate was lower in RSR13-treated than in control animals when animals were O2 supply dependent. The decrease in base excess, arterial pH, and bicarbonate during O2 supply dependence was significantly less after RSR13 than after saline. These findings demonstrate that during O2 supply dependence caused by severe anemia, reducing Hb-O2 binding affinity does not affect VO2 SYS or DO2 CRIT but appears to have beneficial effects on oxidative metabolism and acid base balance.

oxygen affinity; oxygen transport; RSR13; oxygen supply dependency; critical oxygen delivery; anemia


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

TISSUE OXYGENATION depends on the interaction of convective (DO2 CONVEC) and diffusive O2 delivery. Manipulations of either of these principals may set significant limits to tissue O2 availability but may also offer the opportunity to enhance tissue O2 availability (46). Determinants of convective O2 transport are cardiac output (CO), arterial O2 content, and the distribution of blood flow. Diffusive O2 transport is governed by the PO2 gradient between red blood cells (RBCs) and the mitochondria, the O2 conductance and O2 consumption (VO2) of the tissue, and the hemoglobin (Hb)-O2 binding affinity. As the PO2 gradient, the driving force for O2 diffusion, is generated by DO2 CONVEC and Hb-O2 affinity, both the DO2 CONVEC and the position of the Hb-O2 dissociation curve (ODC) represent crucial factors for tissue O2 availability.

Right shifting the ODC, or increasing the O2 tension at which Hb is 50% saturated (P50), favors release of O2 from hemoglobin at higher tissue PO2 (4, 13). As a consequence, the O2 gradient between RBCs and the mitochondria is increased, and more of the O2 transported in the blood is available for consumption in the tissues. This increased O2 gradient between RBCs and mitochondria should allow O2 to diffuse over longer distances or offering more O2 for local mitochondrial metabolism.

Recent research has led to the discovery of new allosteric modifiers of the Hb-O2 affinity (1). RSR13, a 2-[4-[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2- methyl-proprionic acid monosodium salt, reliably reduces the Hb-O2 affinity in vivo. Because RSR13 binds to a site distinct from that of 2,3-diphosphoglycerate, the naturally occurring allosteric modifier of Hb, RSR13 generates an additive rightward shift of the ODC, which should facilitate added O2 release (1). Superfusion of tissues with or infusion of RSR13 reduced hypoxia-induced vasodilation (44), increased tissue PO2 (21), and reduced brain infarct size (43). During maximal exercise, low P50 diminished maximal O2 consumption (VO2 max) (14), whereas an increased P50 by RSR13 enhanced maximal O2 uptake (33). These findings suggest that modifications of the strength of the Hb-O2 bond can effectively alter tissue O2 availability.

Under normal conditions, tissue O2 availability and systemic VO2 (VO2 SYS) remain constant in the event of a fall in DO2 CONVEC because of a proportionate increase in systemic O2 extraction (5). Below a certain value of DO2 CONVEC, also called DO2 CRIT, further increases in O2 extraction are insufficient to compensate for reductions in DO2 CONVEC, and tissue VO2 becomes directly dependent on convective O2 supply. Beyond this point, anaerobic metabolism is initiated, resulting in the production of lactate, reductions in pH and base excess, and accumulation of O2 debt in tissues (35). It was found that reducing the Hb-O2 affinity was most beneficial for tissue oxygenation when DO2 CONVEC was already compromised by mild anemia. Animals with increased P50 demonstrated less hypoxic vasodilation and had significantly lower lactate concentrations than vehicle-treated animals (9).

With this in mind, we hypothesized that right shifting the ODC would potentially facilitate tissue O2 availability in severe anemia, thus lowering the transfusion threshold or extending the safe limits of hemodilution. To date no data are available on the effects of increased P50 on VO2 SYS or DO2 CRIT in the setting of severe anemia. We hypothesized that under conditions of O2 supply dependence (O2SD), when the consumable O2 fraction of DO2 CONVEC is depleted, an increase in diffusive O2 transport induced by an increase in P50 may provide additional O2 to improve tissue oxygenation. For the present experiment we used a model of isovolemic hemodilution to reduce DO2 CONVEC until O2SD occurs. We specifically addressed the questions whether an increased P50 can improve tissue O2 availability, as evidenced by improved VO2 and a lowering of DO2 CRIT, and benefit tissue oxidative metabolism, acidosis, and base excess.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The study protocol was reviewed and approved by the Council of Animal Care of the University of Western Ontario. All animals were acclimatized for 1 wk in our laboratory and housed in cages with food and water ad libitum.

Animal Model

Twenty-four male Sprague-Dawley rats (Charles River; Quebec, Canada) weighing 378 ± 6 g were used in this study. Under halothane anesthesia, all rats were instrumented with an arterial catheter advanced into the aorta via the left carotid artery, and venous catheters were inserted into the left femoral vein and the right jugular vein. A thermodilution CO probe (IT-21 thermocouple, Physiotemp Instruments; Clifton, NJ) was positioned in the aortic arch via the right carotid artery. The cannulas and the thermocouple were tunneled subcutaneously, exteriorized at the interscapular region, and guided into a swivel device. After surgery, rats were allowed to recover for 24 h and were provided with rodent chow and water ad libitum. Catheters were continuously flushed with heparinized (1.6 IU/ml) saline to maintain patency. Analgesia was achieved with a constant infusion of fentanyl (3 µg/h). The fentanyl infusion was terminated the next day, 2 h before the experiment. All animals were randomly assigned to receive either saline or RSR13. The investigator was blinded to the group assignment of the animals and to the results of laboratory measurements (i.e., P50, VO2).

Experimental Protocol

Twenty-four hours after surgery, animals were placed in an airtight chamber, which was connected to a calorimeter system (Oxymax, Columbus Instruments; Columbus, OH). The fractional inspired O2 (FIO2) was produced by mixing room air with pure O2 and monitored continuously with a Miniox-1 oxygen analyzer (Catalyst Research) at the inlet and by the Oxymax within the circuit. The arterial and venous catheters were connected to syringe pumps (Harvard Apparatus; South Natick, MA) for withdrawing blood or infusing plasma, respectively. To provide steady-state conditions, animals were allowed to adapt to the chamber environment for about 30 min before baseline measurements at room air conditions and for another 15 min after FIO2 was elevated from 0.21 to 0.40. After acclimatization and equilibration, baseline measurements of hemodynamics [mean arterial pressure (MAP), CO, and central venous pressure (CVP)], temperature, lactate, P50, Hb concentration, and saturation as well as blood gas analyses were performed at room air and repeated at FIO2 of 0.4. In the treatment group, an RSR13 loading dose (100 mg/kg over 30 min) was administered followed by a continuous infusion of RSR13 (90 mg · kg-1 · h-1). The maintenance dose was allowed to maintain a plateau effect on P50. In the control group (CON), a corresponding volume of saline instead of the RSR13 was infused over the same time period. All measurements were repeated in 30-min intervals until an Hb of 5 g/l was reached; below this threshold 15-min intervals were introduced to record the events around the point of O2-supply dependency in detail. From previous studies with this model we know that increases in lactate and decreases in VO2 SYS develop below an Hb of ~4 g/l (38). Isovolemic hemodilution was started after the baseline data set at FIO2 of 0.4 was collected and continued until the end of the experiment (Fig. 1). After completion of the experiments, a postmortem examination was conducted on each animal to verify the position of all catheters and to inspect the internal organs.


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  		Fig. 1.   Experimental design. RSR13, synthetic allosteric modifier of hemoglobin (Hb); FIO2, inspired O2 fraction; DO2 CRIT, critical O2 delivery; VO2, O2 uptake; MAP, mean arterial pressure; CVP, central venous pressure; CO, cardiac output; BGA, blood gas analysis; P50, O2 tension at which Hb is 50% saturated. BL-0.21 and BL-0.40, baseline measurements on 20% and 40% O2; pre-1, -2, -3, preintervention measured time point; post-1, -2, postintervention measured time points.

O2-Supply Dependency

The principle of isovolemic hemodilution with fresh frozen rat plasma was applied to reduce convective O2 delivery. This way, convective O2 delivery is continuously and progressively lowered to and beyond critical O2 delivery (DO2 CRIT). At the point of DO2 CRIT, DO2 equals VO2, below DO2 CRIT, VO2 becomes O2-supply dependent (5, 35). Therefore, VO2 further decreases if O2 delivery is further reduced. Arterial lactate exhibits an inverse response to hemodilution compared with VO2 SYS. When systemic DO2 approximates the DO2 CRIT, arterial lactate begins to raise indicating insufficient tissue O2 availability and the switch from aerobic to anaerobic metabolism (11, 38).

Critical O2 Delivery

DO2 CRIT was assessed using the model of "VO2-DO2" relationship. According to this model, the relationship between VO2 and DO2 is a biphasic interaction. Briefly, as DO2 to the tissues is decreased, tissue VO2 is maintained by an increase in O2 extraction (O2EX) to match the tissue O2 demand. However, because VO2 cannot exceed DO2 at steady state, it follows that, as DO2 further decreases, VO2 must eventually fall. This inflection point of the VO2-DO2 relationship allows one to determine the level of O2 delivery where hypoxic conditions occur and anaerobic metabolism begins. To assess this point of inflection on the curve of the VO2-DO2 relationship, a dual-line regression analysis was applied. One line was fit to the VO2-DO2 points at high DO2, and a second line was fit to the VO2-DO2 points at low DO2 using linear regression. All possible grouping combinations were examined, and the overall best-fit dual-line regression was chosen when the sum of squared residuals from both lines was minimized. The intersection of the two lines determines the critical O2EX ratio from which the critical DO2 is then derived by drawing a line through this intersection perpendicular to the x-axis. The intersection of the perpendicular and the x-axis is the DO2 CRIT (34).

Isovolemic Hemodilution

Rat plasma was collected from fresh donor rat blood. For blood collection, donor rats were anesthetized with pentobarbital (6.5 mg/100 g body wt ip). Animals were laparotomized under sterile conditions. The bowel was moved aside to expose the abdominal aorta. The aorta was punctured using a venipuncture catheter (Quickcath, Baxter). Blood was collected in a sterile syringe containing citrate, phosphate, dextrose, and adenosine solution (CPDA-1) as anticoagulant. The blood was then centrifuged 3,000 g for 10 min, and the plasma fraction was separated, frozen, and stored until used. In a previous study, this procedure was evaluated and shown to exclude bacterial contamination (38). For hemodilution, rat plasma, freshly thawed and warmed to 37°C, was infused (Harvard Apparatus pump) through a 40-µm transfusion filter via the jugular vein catheter. Simultaneously and at the same rate, blood was withdrawn with another syringe pump from the arterial catheter. The initial rate of the isovolemic hemodilution down to a Hb of 5 g/l was 8 ml/h; at a Hb concentration of 5 g/l, hemodilution speed was then reduced to 6 ml/h and maintained at this rate until the end of the experiment.

Measurements and Calculations

Hemodynamics. For monitoring MAP and CVP, the arterial and jugular lines were connected to pressure transducers (Uniflow; Baxter) joined to a multichannel amplifier recording system (HP; Mississauga, CA). CO was measured by the thermodilution technique by injecting 0.3 ml of saline at room temperature via the jugular vein (9). The thermocouple signal was converted by a Cardiotherm 500 AC-R CO computer (Columbus Instruments; Columbus, OH).

Oxygen transport. Hb concentrations and Hb-O2 saturations were assessed using a cooximeter (OSM-II Hemoximeter, Radiometer). Blood gases were measured from arterial and central venous blood samples using a blood gas analyzer (ABL 520, Radiometer) linked with a hemoximeter (OSM3, Radiometer). After withdrawal, the blood samples were immediately placed on ice. VO2 SYS was directly measured by an Oxymax system (Oxymax, Columbus Instruments). By this system, a constant air flow (FIO2: 0.4) at 3.5 l/min was delivered into the box containing the animal. Gas from the outlet limb of the box was sampled by a paramagnetic O2 sensor for analysis of O2 content and then by an infrared CO2 analyzer. VO2 SYS was measured from the reduction of O2 content within the system and displayed online. Five consecutive values obtained over a 60-s period were averaged to determine VO2 SYS at an individual time point. DO2, O2EX, and O2 content were calculated using standard equations.

P50 measurements. The P50 values were obtained from central venous blood samples analyzed by the ABL 520. In a previous study (9), we validated the accuracy of the P50 readings obtained from the ABL 520 to values obtained by multipoint tonometry technique (IL 237 Tonometer, Instrumentation Laboratories; Lexington, MA) as a reference.

Lactate, bicarbonate, base excess, and pH. Lactate concentrations were measured by means of a quantitative, enzymatic method (Paramax Analytical System, Baxter). Bicarbonate, base excess, and pH values were calculated by the ABL 520 analyzer.

Statistics

For statistical analysis of the data, SigmaStat 1.0 software (Jandel; San Raphael, CA) was used. A two-way ANOVA for repeated measurements was applied to the data completed by a post hoc analysis (Student-Newman-Keuls method) or t-tests, followed by the Bonferroni procedure where applicable. For all comparisons, differences were considered significant at a P value of <0.05. Data are presented as means ± SE if not indicated differently.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Twenty-four hours after insertion of the catheters and CO thermistor, none of the animals showed signs of infection such as reduced activity, piloerection, and exudations around eyes and nose. Postmortem examination exhibited normal thoracic and abdominal organs without signs of infection, ischemia, or necrosis.

P50. The continuous infusion of RSR13 (loading dose plus adjusted maintenance dose) produced a consistent and significant (P < 0.05) increase in P50 throughout the experiment (Fig. 2). In control animals, baseline P50 started at 36.2 ± 1.7 mmHg and remained unchanged at all subsequent time points. In the RSR13-treated animals, P50 was elevated from a baseline of 35 to 45 mmHg after the loading infusion and was maintained at this level for the remainder of the experiment by adjusting the maintenance dose, i.e., by stepwise reduction during hemodilution (Fig. 2). The average difference in P50 between the CON and RSR13 groups during the continuous infusion of RSR13 was 11 mmHg.


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  		Fig. 2.   Comparison of P50 from rats that received an infusion of vehicle only (CON) (n = 12) or from rats that received an infusion of RSR13 (RSR13) (n = 12). Values are given as means ± SE; * Significantly different from control; P < 0.05.

Oxygen transport. Arterial Hb-O2 saturations (SaO2) were comparable in both groups (CON: 93 ± 0.3%; RSR13: 93 ± 0.3%) at room air and increased after exposure to elevated FIO2 of 0.40 (CON: 99 ± 0.1%; RSR13: 99 ± 0.1%). The bolus infusion of RSR13 caused a significant (P < 0.05), but small and temporary, reduction of SaO2 (CON: 99 ± 0.2; RSR13: 96 ± 0.5%); otherwise there was no difference in SaO2 between or within groups compared with baseline (BL on 40% supplemental O2, BL-0.40) (Fig. 3A). Venous Hb-O2 saturations (SvO2) were similar between groups at room air (CON: 59 ± 1%; RSR13: 60 ± 1%) and at FIO2 of 0.40 (CON: 67 ± 2%; RSR13: 69 ± 2%) (Fig. 3B). During hemodilution SvO2 decreased in both groups compared with BL-0.40 but was lower in the RSR13-treated animals. The difference reached significance (P < 0.05) at measured time point 2 preintervention (CON: 56 ± 2% vs. RSR13: 46 ± 2%), DO2 CRIT (CON: 56 ± 4% vs. RSR13: 44 ± 2%), and time point 2 postintervention (CON: 51 ± 3% vs. RSR13: 43 ± 2%) (Fig. 3B). Arterial (PaO2) and venous O2 tensions (PvO2) were comparable between groups at room air and increased at FIO2 0.40 to the same extent in both groups. During hemodilution PaO2 showed a tendency for higher values in the RSR13 group but was only significant (P < 0.05) at the end of the experiment (CON: 181 ± 16 mmHg; RSR13: 204 ± 11 mmHg) (Fig. 4A). PvO2 remained higher during hemodilution in RSR13 than in saline-treated animals. Over time, however, PvO2 values fell below baseline in both groups (P < 0.05) (Fig. 4B). DO2 CRIT did not differ between groups; DO2 CRIT was 3.5 ± 0.3 ml · min-1 · 100 g-1 (CON) and 3.4 ± 0.2 ml · min-1 · 100 g-1 (RSR13-treated animals) (Fig. 5).


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  		Fig. 3.   A: comparison of arterial O2 saturations (SaO2) between saline and RSR13-infused animals. B: time course of venous O2 saturations (SvO2) in saline and RSR13-treated animals. Values are expressed as means ± SE. * Significance for treatment effect between groups (P < 0.05); # significantly different from baseline within the control animals (P < 0.05); § significantly different from baseline within RSR13 group (P < 0.05).



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  		Fig. 4.   A: arterial O2 tensions (PaO2) of saline and RSR13-infused animals. B: time course of venous O2 tensions (PvO2) in saline and RSR13-treated animals. Values are expressed as means ± SE. * Significance for treatment effect between groups (P < 0.05); # significantly different from baseline within the control animals (P < 0.05); § significantly different from baseline within RSR13 group (P < 0.05).



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  		Fig. 5.   Effect of increased P50 on DO2 CRIT in severe anemia. (n = 12 in each group).

Both groups commenced the experiment with almost identical arterial Hb concentrations. The continuous isovolemic hemodilution produced the same profile of hemodilution throughout the experiment in both groups (Table 1). As a consequence of hemodilution, DO2 CONVEC progressively declined. The reduction in DO2 CONVEC index (DO2I) was equivalent in both groups (Table 1). Analogous to the reduction of O2 delivery, systemic VO2 index (VO2I) decreased from 2.2 ml · min-1 · 100 g-1 in both groups to 0.8 ± 0.2 ml · min-1 · 100 g-1 in the control and 0.7 ± 0.2 ml · min-1 · 100 g-1 in the RSR13 animals at the conclusion of the study (Table 1). Systemic O2EX progressed in the opposite direction and showed a comparable increase in both groups reaching a plateau at DO2 CRIT (Table 1).

                              
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  		Table 1.   Oxygen metabolism and hemoglobin concentrations

Hemodynamics. Both groups commenced the experiment with equivalent MAP (CON: 113 ± 2 mmHg; RSR13: 114 ± 2 mmHg). Elevating FIO2 to 0.4 had no effect on blood pressure. During hemodilution, MAP continuously decreased in both groups until the end of the experiment (CON: 71 ± 2 mmHg; RSR13: 72 ± 5 mmHg) (Fig. 6A). Systemic vascular resistance index (SVRI) was also similar between groups at study onset both at room air (CON: 142 ± 6; RSR13: 134 ± 3 dyn · s-1 · cm5 · 100 g) and at elevated FIO2 of 0.4 (CON: 154 ± 7; RSR13: 147 ± 7 dyn · s-1 · cm5 · 100 g). While animals were hemodiluted, SVRI decreased until DO2 CRIT was reached and then increased in both groups (P < 0.05) (Fig. 6B). Cardiac index (CI) showed comparable values between groups at the beginning of the experiment (CON: 62 ± 2; RSR13: 67 ± 1 ml · min-1 · 100 g-1) (Fig. 6C). Raising the FIO2 did not affect CI in either group. Isovolemic hemodilution resulted in an increase in CI in both groups until DO2 CRIT occurred. During O2-supply dependency CI dropped in both groups.


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  		Fig. 6.   Effects of hemodilution on hemodynamic parameters in control (CON) and in animals with increased P50 (RSR13). A: MAP. B: systemic vascular resistance index (SVRI). C: cardiac index (CI). Values are expressed as means ± SE. # Significantly different from baseline within the control animals (P < 0.05); § significantly different from baseline within RSR13 group (P < 0.05).

Metabolic parameters. At baseline, lactate concentrations were comparable between groups (CON: 0.6 ± 0.04; RSR13: 0.8 ± 0.1 mmol/l) and remained unchanged after elevation of FIO2 to 0.4. At time point 2 preintervention during hemodilution, lactate started to increase and was significantly higher in the saline than in the RSR13-treated animals (1.6 ± 0.2 vs. 0.9 ± 0.2 mmol/l). As hemodilution progressed, lactate continued to rise with higher values in the control animals (Fig. 7A). Base excess (CON: 6.3 ± 0.47 mmol/l; RSR13: 5.7 ± 0.3 mmol/l) and bicarbonate (HCO<UP><SUB>3</SUB><SUP>−</SUP></UP>) (CON: 30 ± 0.5 mmol/l; RSR13: 29 ± 0.3 mol/l) were not different between groups at baseline (Fig. 7B). Throughout hemodilution base excess and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> increased to the same extent in both groups and returned toward baseline values around the point of DO2 CRIT. Beyond DO2 CRIT, when the animals were O2-supply dependent, both base excess and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> (Fig. 8A) fell further, but the drop of both parameters was significantly greater in the saline than in the RSR13-treated animals (P < 0.05). Arterial pH was comparable between the groups at baseline (CON: 7.45 ± 0.006; RSR13: 7.45 ± 0.004) and remained unchanged in both groups during hemodilution down to DO2 CRIT. After the animals were in O2-supply dependency, the pH started to decrease in the saline-treated group and was significantly (P < 0.05) lower at the end of the study (time point 2 postintervention), whereas arterial pH in the RSR13-treated animals was maintained at baseline level throughout the experiment (Fig. 8B).


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  		Fig. 7.   A: arterial lactate concentrations in animals with regular (CON) and increased P50 (RSR13). Dotted line marks the upper limit of the normal range. B: time course of base excess in saline and RSR13-infused animals. Values are expressed as means ± SE. * Significance for treatment effect between groups (P < 0.05); # significantly different from baseline within the control animals (P < 0.05); § significantly different from baseline within RSR13 group (P < 0.05).



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  		Fig. 8.   A: bicarbonate concentrations of saline and RSR13-infused animals. B: comparison of arterial pH of animals with regular P50 (CON) and increased P50 (RSR13). Values are expressed as means ± SE. * Significance for treatment effect between groups (P < 0.05); # significantly different from baseline within the control animals (P < 0.05); § significantly different from baseline within RSR13 group (P < 0.05).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Reductions in DO2 CONVEC may reduce tissue O2 availability, particularly when O2EX as a compensatory mechanism to decreased DO2 CONVEC is maximized. As a result, VO2 becomes supply dependent. In severe anemia, the transfusion of fresh RBCs rapidly terminates this state of O2SD and restores DO2 CONVEC (38). As an alternative to restoring DO2 CONVEC by transfusion of blood, we hypothesized that an increase in diffusive O2 delivery by reducing the Hb-O2 affinity may release additional O2 from Hb when DO2 CONVEC is already depleted.

We investigated whether an increase in P50 can lower DO2 CRIT or improve VO2 SYS during O2SD induced by severe anemia. In a model of progressive isovolemic hemodilution, hemodynamics, O2 transport, and metabolic parameters as well as systemic DO2 CRIT and VO2 SYS were compared between a control and a treatment group with elevated P50.

We found that a continuous infusion of RSR13 adjusted to the declining Hb concentration produced a constant increase in P50. Increasing FIO2 maintained SaO2 and PaO2 equivalent in both groups. SvO2 levels were lower and PvO2 higher during hemodilution and at DO2 CRIT in animals with high P50. However, despite these favorable conditions of O2 availability, VO2 SYS, O2EX, and DO2 CRIT were not significantly different between the control and elevated P50 group. In addition, we observed that at or below DO2 CRIT lactate, base excess, bicarbonate, and arterial pH were less deranged in the elevated P50 than in the control group.

In O2-supply dependence, VO2 becomes limited by constraints in diffusive O2 transport as capillary PO2 falls below a critical level (34, 35, 41). Elevating P50 by about 12 mmHg, which is comparable to the 11-mmHg increase in our study, theoretically predicts an end-capillary PO2 that is ~15 mmHg higher than at a normal P50 (6). Such increases in capillary PO2 have been reported to assist diffusion and thus aiding tissue O2 availability. Physiological adaptive mechanisms such as the effects of elevated temperature, low pH, or increased RBC content of 2,3-DPG that favors O2 release by decreasing Hb-O2 binding affinity support this hypothesis (31).

Effects of altered P50. In contrast to high P50, low P50 impaired tissue O2 availability by limiting diffusion. Low P50 blood was shown to reduce bile flow and PvO2 (3), increased mortality after hemorrhagic shock (28), and decreased myocardial contractility (2). Gastric intramucosal pH fell after transfusion of blood with low P50 (29). At maximal exercise, VO2 of dog gastrocnemius muscle at constant DO2 CONVEC dropped by 17% when perfused with low P50 RBCs (15). This apparent importance of P50 for O2 uptake in the study by Hogan et al. (15) offers the possibility that, unlike increased Hb-O2 affinity, reduced Hb-O2 affinity could improve O2EX by elevating the capillary PO2 gradient.

All animals with increased P50 subjected to global ischemia and cardiopulmonary bypass returned to normal sinus rhythm and doubled CO (22). Right shifting the ODC also improved the recovery of stunned myocardium (32), reduced anemia-induced brain damage (12), and improved neurological outcome from brain ischemia (27). Although tissue PO2 was not measured in these studies, the benefits were attributed to enhanced O2 delivery with increased capillary and tissue PO2 induced by the right-shifted ODC. Curtis et al. (6) observed increased venous and tissue PO2 in the animals with increased P50, and Watson et al. (43) showed that reduced cerebral infarct size correlated with higher brain O2 tensions. In our study, PvO2 was also significantly higher and venous Hb-O2 saturations were significantly lower in the RSR13-treated animals suggesting increased O2 release. In contrast to Curtis et al. (6), where SaO2 dropped to ~91%, we ensured pulmonary O2 loading by increased FIO2, which maintained SaO2 in the high P50 group and produced slightly higher PaO2. Because the shift in P50 was about 12 mmHg in Curtis' and our study, we assume that, analogous to Curtis' findings, the increased PvO2 observed in our experiments are probably associated with a similar increase in tissue PO2 in the RSR13-treated group in our experiments.

The improved diffusive O2 transport by high P50 may enhance O2 supply to the mitochondria and lead to a reduction in anaerobic metabolism particularly in marginally perfused areas during anemia. As a consequence, metabolic parameters such as lactate and arterial pH should be more stable in animals with elevated P50 when DO2 CONVEC is limited. Kimura et al. (23) measured lower lactate concentrations and better preserved tissue ATP content in anemic animals exchange transfused with 2,3-DPG-enriched RBCs. During low-flow myocardial ischemia, right shifting the ODC by RSR13 halted the decline of intracellular pH and preserved high-energy phosphates (45). Previously, we also observed lower lactate concentrations during mild anemia when P50 was elevated (9). In this study, lactate concentrations increased in both groups as anemia progressed but were lower in RSR13-treated compared with control animals at or below DO2 CRIT. Base excess, bicarbonate, and pH were significantly less affected during OSD in high P50 animals. Although the values were significantly different from controls, the positive impact of increased P50 on the metabolic parameters was mostly a mitigation of the negative impact of tissue hypoxia cushioning the derangement in OSD, possibly by a more homogenous O2 distribution that might have reduced the number or the size of dysoxic areas. Nevertheless, this mitigating effect appears to be too little to improve total systemic O2 availability.

Despite the theoretical improvements of diffusion by increased capillary PO2 and facilitated O2 release, the increase in P50 did not significantly improve either O2EX or DO2 CRIT. This was a surprising result, because we and other investigators previously observed that increasing P50 could improve tissue oxygenation and VO2 in various tissues under different conditions.

Possible explanations. One interpretation of our observations may be related, at least in part, to the nature of the shift of the ODC. Lowering Hb-O2 affinity by RSR13 does not induce a parallel right shift but causes a shift of the curve associated with a reduction of the Hill coefficient (33). Therefore, the increase in P50 by 11 mmHg, as found in our study, produces an increase in PvO2 by ~12-15 mmHg in the steep middle section of the ODC, but the difference in PvO2 might become very small in the low saturation part because the curves of all hemoglobins finally converge. Hence, arteriovenous unloading might be similar at the critical capillary PO2 regardless of P50, resulting in an increase in DO2 CRIT probably too small to be detected by our methodology. On the other side, the average PvO2 during hemodilution and around DO2 CRIT was about 8 mmHg higher in the high P50 than in the control group (Fig. 4). Considering that this PvO2 is in the upper to supranormal range and that the PvO2 difference matches the scale of PO2 gradients found between A4 arterioles, capillaries, and V1 venules to tissue PO2 (19), tissue O2 availability should have been improved by the shift of ODC in the present study.

Others have suggested (36) that arteriovenous O2 unloading becomes insensitive to P50 only at a capillary PO2 below 5 mmHg. In the present study, however, PvO2 values (CON: 41 mmHg; RSR13: 49 mmHg) were higher and even higher than those reported by Curtis et al. (CON:~20 mmHg; RSR13:~27 mmHg) (6) who measured both PvO2 and tissue PO2 (CON: 24 mmHg; RSR13: 33 mmHg) during ischemia induced O2 supply dependence. Because of these findings, it is unlikely that, in our experiments, capillary PO2 was lower or close to 5 mmHg (36). Nevertheless, it appears that, under the conditions of severe anemia, either the PO2 gradients were still inappropriate or other factors than PO2 gradients had more influence on O2 distribution in anemia-induced O2SD.

There is evidence that VO2 by the arteriolar microcirculation (30) or functional shunting of O2 within the microcirculatory cascade may be important for tissue O2 availability. Duling et al. (8) demonstrated that longitudinal gradients in PaO2 do occur, and some of the O2 exits the circulation creating periarteriolar PO2 values of ~30 mmHg. Intaglietta et al. (19) concluded that up to one-third of the arteriolar O2 can exit the arteriolar tree before arrival at the capillaries. Possible recipients are the surrounding tissue, capillaries, and even venules bypassing the tissue or capillaries. Under normal conditions, shunting of O2 away from arterioles to parallel venules was found to be negligible (19, 37) but under conditions of facilitated O2 release from Hb by increased P50 creating higher PO2 gradients, diffusing shunting may be relevant and would help to explain elevated PvO2 but unchanged DO2 CRIT and O2EX in extreme anemia.

The influence of small differences in the O2 unloading rate and capillary PO2 may also be determined by erythrocyte transit time, RBC spacing, diffusion distance, and functional capillary density. In severe anemia, the intererythrocytic distance may be enhanced (19). Because most of the O2 in blood is bound to Hb in RBCs, and because O2 solubility in plasma is low, increased plasma gaps or increased plasma layers between or around RBCs may reduce the capillary surface area available for O2EX. The gradient for O2 across the capillary would decrease, and the diffusing capacity would be diminished (10). The transfusion of cell-free Hb in anemia-induced O2SD increased VO2 SYS and lowered lactate (38). It was concluded that cell-free Hb increases the O2 diffusion capacity of blood and facilitates O2 transport through enlarged plasma gaps to the capillary wall. Such an increased resistance to diffusion by enlarged plasma gaps may have counterbalanced the effects of reduced Hb-O2 binding affinity during severe anemia.

Extreme anemia as in this study is associated with high blood velocity, reduced lineal density, and a limited RBC supply rate in the microcirculation. These effects can decrease RBC transit time thereby minimizing the temporal window for O2EX (16). The importance of RBC transit time has been reported for both muscle and coronary circulation (24) In our study with Hb of about 3 g/dl at DO2 CRIT, shortened transit times may be of particular importance because O2 off-loading kinetics for Hb are two times slower than O2 loading on Hb (24). This may have equilibrated the effects of eased O2 release and resulted in a net reduction of the overall diffusing capacity, which could at least partially explain the unchanged PvO2 and VO2 in our study. Mild anemia has been shown to maintain or improve erythrocyte flux in capillaries and reduce the heterogeneity of erythrocyte distribution resulting in lowered DO2 CRIT and higher O2EX ratio, indicating improved O2EX capabilities (40). This positive impact is attributed to alterations in blood rheology, in particular to reduced blood viscosity. However, when hemodilution is continued beyond the transfusion trigger, i.e., below a Hb of ~7 g/dl, blood viscosity is reduced by half and is similar to plasma viscosity. Below this point, CO does not increase further as viscosity is lowered due to an increase in vascular resistance aimed at maintaining central blood pressure (39). This is in line with the time course of the CI and systemic vascular resistance in our study. This increase in vascular resistance with the microcirculation as the principle site of constriction lowers capillary pressure resulting in diminished functional capillary density (26). These interactions of blood viscosity, CI, and systemic vascular resistance may derecruit a significant number or certain groups of capillaries, which would diminish the O2 exchange surface and the O2 diffusing capacity. Low viscosity-induced alterations in microcirculatory blood flow may also favor effects such as plasma skimming resulting in a redirection of RBC flow away from nutritional to nonnutritional channels (7) reducing functional capillary density. These effects could occur well before the limits of capillary extraction were reached, rendering the DO2 CRIT possibly more dependent on blood rheology, specifically on blood viscosity, and local hemodynamics than on the position of the ODC when Hb is extremely low (20).

Other investigators have proposed that increased heterogeneity of O2 delivery may impair O2EX (25). Walley (42) found that incomplete O2EX can be explained by a mismatch of O2 demand to O2 supply and diffusion limitation. Thus a capillary bed with heterogeneous flows and transit times would exhibit a lower critical O2EX ratio than tissue with homogenous microcirculatory flows and transit times (17). The finding by Humer et al. (17) of increased heterogeneity of capillary transit times in endotoxemic pigs confirm Walley's hypothesis. That DO2 heterogeneity does occur has been demonstrated in ischemic rat hearts where NADH fluorescence showed patchy areas of severe hypoxia immediately adjacent to well-oxygenated areas (18).

In summary, this study demonstrates that in conditions of extreme anemia, right shifting the ODC may mitigate the tissue's oxygen debt as indicated by the time course of the metabolic parameters. But the O2 additionally released from Hb at very low Hb concentrations is either insufficient in quantity to completely compensate the O2 deficit caused by a severely compromised DO2 CONVEC or does not reach the tissue areas in need for O2 because of a limited diffusion capacity caused by severe anemia. It is likely that other factors such as microcirculatory perfusion heterogeneities and changes in microvascular blood rheology occur in severe anemia, which mostly counterbalance the positive effects reduced Hb-O2 affinity on tissue oxygenation. Thus the approach to increase diffusive O2 transport by reducing Hb-O2 binding affinity alone does not significantly improve tissue O2 availability in extreme anemia.


    ACKNOWLEDGEMENTS

We acknowledge the blood gas laboratory of the London Health Sciences Centre, South Street Campus, for analyzing the numerous blood samples and Marcela White for the excellent technical assistance. The authors gratefully thank Allos Therapeutics (Denver, CO) for providing RSR13 and financial support for the experiments.


    FOOTNOTES

Address for reprint requests and other correspondence: I. Chin-Yee, London Health Sciences Centre, Westminster Campus, 800 Commissoners Road East, London, Ontario, Canada N6A 4G5 (E-mail: ian.chinyee{at}lhsc.on.ca).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

First published March 21, 2002;10.1152/ajpheart.01066.2001

Received 5 December 2001; accepted in final form 13 March 2002.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Heart Circ Physiol 283(1):H92-H101
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